HIV infection leads to CD4 lymphopenia and immunosuppression, which can be successfully improved with antiretroviral therapy (ART) in the majority of cases. Approximately 20 percent of HIV patients initiated on ART may develop an aberrant immune response known as immune reconstitution syndrome (IRIS). IRIS encompasses the paradoxical worsening of the manifestations of underlying opportunistic diseases (paradoxical IRIS) or the abrupt presentation of previously occult opportunistic disease (unmasking IRIS) in patients who recently started ART. Symptoms of IRIS can range from uncomplicated localized reactions to severe and systemic manifestations. Clinical studies have identified two main risk factors for IRIS: severe CD4 lymphopenia and the presence of opportunistic infections even if clinically silent (M. tuberculosis, M. avium complex, C. neoformans or other fungi, or viral pathogens) prior to ART initiation. The pathogenesis of IRIS in HIV infection remains unclear and there is no animal model that adequately mimics the clinical observations. In order to study the clinical predictors, biomarkers and pathogenesis of IRIS we are conducting a large prospective observational clinical trial of ART-naive HIV+ patients with severe CD4 lymphopenia (<100 cells/L) who are followed longitudinally after initiation of ART. The study is being conducted both in the US and in Kenya. Our collaborators in Dr Sher's laboratory in LPD are also developing a murine model of mycobacterial IRIS. Preliminary findings from a pilot human study of HIV+ patients who were ART-naive and developed IRIS and were compared with HIV+ patients who did not develop IRIS despite having similar opportunistic infections, suggest that two easily accessible tests from clinical laboratories (CRP and D-dimer) may be useful to predict or diagnose IRIS. Further evaluation of these biomarkers in larger prospective studies is warranted. In the same cohort we evaluated the phenotype of T cells at baseline (pre-ART) and around the IRIS events. T cells from IRIS patients bore a highly activated phenotype (effector cells with high PD-1 expression) both pre-ART and at the time of IRIS, showing evidence of profound antigenic stimulation. IRIS patients also had a slower recovery of naive CD4 T cells following the IRIS events. These findings suggest a significant antigenic drive of T cell activation and expansion that becomes dysregulated as severe immunosuppression reverses. Despite the significant improvement of morbidity and mortality in HIV infection in the ART era, mortality in HIV+ patients is still in excess of what is expected based on age and strongly relates to the degree of immunodeficieny as measured by CD4 T cell counts. Immune-based therapies are thus still being pursued with the objective to improve immune restoration in CD4 lymphopenic states. IL-7 is a cytokine that plays an essential role in thymopoiesis and in post-thymic maturation, differentiation, proliferation and survival of T cells, making it an attractive candidate for immunotherapy of lymphopenias. Preliminary studies have shown that IL-7 is well tolerated in HIV infection at doses that show promising biologic activity (T cell cycling and T cell count increases). IL-7 immunotherapy is currently being studied in phase II studies in HIV and in idiopathic CD4 lymphopenia.